Quantitative pharmacophore models with inductive logic programming

Three-dimensional models, or pharmacophores, describing Euclidean constraints on the location on small molecules of functional groups (like hydrophobic groups, hydrogen acceptors and donors, etc.), are often used in drug design to describe the medicinal activity of potential drugs (or ‘ligands’). This medicinal activity is produced by interaction of the functional groups on the ligand with a binding site on a target protein. In identifying structure-activity relations of this kind there are three principal issues: (1) It is often difficult to “align” the ligands in order to identify common structural properties that may be responsible for activity; (2) Ligands in solution can adopt different shapes (or `conformations’) arising from torsional rotations about bonds. The 3-D molecular substructure is typically sought on one or more low-energy conformers; and (3) Pharmacophore models must, ideally, predict medicinal activity on some quantitative scale. It has been shown that the logical representation adopted by Inductive Logic Programming (ILP) naturally resolves many of the difficulties associated with the alignment and multi-conformation issues. However, the predictions of models constructed by ILP have hitherto only been nominal, predicting medicinal activity to be present or absent. In this paper, we investigate the construction of two kinds of quantitative pharmacophoric models with ILP: (a) Models that predict the probability that a ligand is “active”; and (b) Models that predict the actual medicinal activity of a ligand. Quantitative predictions are obtained by the utilising the following statistical procedures as background knowledge: logistic regression and naive Bayes, for probability prediction; linear and kernel regression, for activity prediction. The multi-conformation issue and, more generally, the relational representation used by ILP results in some special difficulties in the use of any statistical procedure. We present the principal issues and some solutions. Specifically, using data on the inhibition of the protease Thermolysin, we demonstrate that it is possible for an ILP program to construct good quantitative structure-activity models. We also comment on the relationship of this work to other recent developments in statistical relational learning. Editors: Tamás Horváth and Akihiro Yamamoto     

An aldose reductase inhibitor and aminoguanidine prevent vascular endothelial growth factor expression in rats with long-term galactosemia

OBJECTIVE: To study the effects of an aldose reductase inhibitor (ARI-509, Wyeth-Ayerst, Princeton, NJ) and aminoguanidine (AMG), agents that have been reported to prevent or delay diabetic retinopathy, on retinal vascular abnormalities and the immunocytochemical expression in the retina of vascular endothelial growth factor (VEGF) in rats maintained for up to 2 years on a 50% galactose diet. METHODS: Albino rats were placed on a control diet, a diet containing 50% galactose, or the 50% galactose diet containing either ARI-509 or AMG. Treatment with ARI-509 or AMG was initiated at the beginning of the experiment or after 12 months of galactose feeding. After 22 to 24 months, the rats were killed and the retinal vasculature from half of one eye was isolated by trypsin-elastase digestion for semiquantitative evaluation of retinal vascular lesions. The other half of the retina was prepared for immunocytochemistry and stained for the presence of VEGF, factor VIII, vimentin, and glial fibrillary acidic protein. Red blood cells, sciatic nerves, and a portion of the retina from the second eye were assayed for glucose, galactose, fructose, sorbitol, galactitol, and myo-inositol. Red blood cells were also assayed for galactosylated hemoglobin. RESULTS: Galactose-fed animals developed a vascular retinopathy characterized by severe cellular loss in the retinal capillaries and intensification of periodic acid-Schiff staining of the vascular basement membranes. Some animals also displayed dilation and hypercellularity of vessels in the posterior retina. These changes were substantially reduced in animals receiving ARI-509 from the beginning of the galactose diet, but were unaffected in all of the other treatment groups. None of the rats receiving ARI-509 or AMG treatment, whether initiated from the onset or after 12 months of galactosemia, demonstrated VEGF immunoreactivity. With the exception of the animals receiving ARI-509 from the beginning of the experiment, all of the galactose-fed animals developed dense cataracts within 6 weeks of the beginning of the galactose diet. Galactitol levels in animals receiving ARI-509 were 86% to 93% lower in red blood cells, retina, and sciatic nerve than those in the other galactose-fed groups. CONCLUSIONS: Although ARI-509 and AMG have different abilities to delay or prevent the diabetic-like retinopathy in galactosemic rats, even when substantial retinal microvascular acellularity occurs, both drugs prevent the immunocytochemical expression of VEGF. These results suggest that factors other than hypoxia may be responsible for VEGF expression in the retina, and that aldose reductase inhibitors and AMG have potential roles in preventing such expression and, thus, perhaps preventing retinal neovascularization.     

MANAGING DISTRIBUTED COMPUTING Five Practices for Success

Management of distributed environments requires corporate IS managers to shift from being operators of a central utility to facilitators who can recognize the synergy among loosely related groups of users. Success depends on the development of new ways of visualizing and measuring the service delivery process.     

Simulation of magnetic component models in electric circuitsincluding dynamic thermal effects

It is essential in the simulation of power electronics applications to model magnetic components accurately. In addition to modeling the nonlinear hysteresis behavior, eddy currents and winding losses must be included to provide a realistic model. In practice the losses in magnetic components give rise to significant temperature increases which can lead to major changes in the component behavior. In this paper a model of magnetic components is presented which integrates a nonlinear model of hysteresis, electro-magnetic windings and thermal behavior in a single model for use in circuit simulation of power electronics systems. Measurements and simulations are presented which demonstrate the accuracy of the approach for the electrical, magnetic and thermal domains across a variety of operating conditions, including static thermal conditions and dynamic self heating     

What We Mean by Future-Proofing

Perhaps the most powerful claim that advocates of fiber can make,on top of the massive bandwidthfiber makes possible today, is that fiber is future-proof. That is, the fiber that is laid today can be upgraded so that the same strands of glass can carry massively more bandwidth in the future.     

Fungal carriage in lizards

The occurrence of fungi was investigated in the gut of 200 common garden lizards (Agama agama). The most important pathogenic fungus isolated was Basidiobolus haptosporus, an aetiological agent of subcutaneous zygomycosis. It was recovered from the intestinal contents of 112 (56%) lizards. Other important fungi isolated included Aspergillus spp. in 24 (12%) lizards, Candida spp. in 12 (6%), Penicillium spp. in 12 (6%) and Fusarium spp. in 12 (6%). Mucor spp. were isolated from eight (4%) male lizards only. Agamid lizards are plentiful in rural and urban areas of Nigeria. As they live in close vicinity to man, they are likely to play an important role in the spread of disease that may be caused by these fungi and its transmission to man. None of the animals investigated that yielded fungal cultures revealed any external fungal infection.     

Running programs backwards: The logical inversion of imperative computation

Imperative programs can be inverted directly from their forward-directed program code with the use of logical inference. The relational semantics of imperative computations treats programs as logical relations over the observable state of the environment, which is taken to be the state of the variables in memory. Program relations denote both forward and backward computations, and the direction of the computation depends upon the instantiation pattern of arguments in the relation. This view of inversion has practical applications when the relational semantics is treated as a logic program. Depending on the logic programming inference scheme used, execution of this relational program can compute the inverse of the imperative program. A number of nontrivial imperative computations can be inverted with minimal logic programming tools.